Diaminopyridine-based potent and selective mps1 kinase inhibitors binding to an unusual flipped-Peptide conformation.

Monopolar spindle 1 (Mps1) is an attractive cancer drug target due to the important role that it plays in centrosome duplication, the spindle assembly checkpoint, and the maintenance of chromosomal stability. A design based on JNK inhibitors with an aminopyridine scaffold and subsequent modifications identified diaminopyridine 9 with an IC50 of 37 nM. The X-ray structure of 9 revealed that the Cys604 carbonyl group of the hinge region flips to form a hydrogen bond with the aniline NH group in 9. Further optimization of 9 led to 12 with improved cellular activity, suitable pharmacokinetic profiles, and good in vivo efficacy in the mouse A549 xenograft model. Moreover, 12 displayed excellent selectivity over 95 kinases, indicating the contribution of its unusual flipped-peptide conformation to its selectivity.

[1]  R. Syed,et al.  Discovery of highly selective and potent p38 inhibitors based on a phthalazine scaffold. , 2008, Journal of medicinal chemistry.

[2]  Yusuke Nakamura,et al.  Expression profiles of non-small cell lung cancers on cDNA microarrays: Identification of genes for prediction of lymph-node metastasis and sensitivity to anti-cancer drugs , 2003, Oncogene.

[3]  Yusuke Nakamura,et al.  Genome-wide gene expression profile analysis of esophageal squamous cell carcinomas. , 2006, International journal of oncology.

[4]  Chaohong Sun,et al.  Aminopyridine-based c-Jun N-terminal kinase inhibitors with cellular activity and minimal cross-kinase activity. , 2006, Journal of medicinal chemistry.

[5]  Leonard M. G. Chavas,et al.  Crystal Structure of the Catalytic Domain of the Mitotic Checkpoint Kinase Mps1 in Complex with SP600125* , 2008, Journal of Biological Chemistry.

[6]  Yusuke Nakamura,et al.  Genome-wide profiling of gene expression in 29 normal human tissues with a cDNA microarray. , 2002, DNA research : an international journal for rapid publication of reports on genes and genomes.

[7]  E. Casale,et al.  Through the "gatekeeper door": exploiting the active kinase conformation. , 2010, Journal of medicinal chemistry.

[8]  L. Tabernero,et al.  Biophysical and X-ray crystallographic analysis of Mps1 kinase inhibitor complexes. , 2010, Biochemistry.

[9]  Riccardo Colombo,et al.  Synthesis and SAR of new pyrazolo[4,3-h]quinazoline-3-carboxamide derivatives as potent and selective MPS1 kinase inhibitors. , 2011, Bioorganic & medicinal chemistry letters.

[10]  L. Wodicka,et al.  A small molecule–kinase interaction map for clinical kinase inhibitors , 2005, Nature Biotechnology.

[11]  Antonella Isacchi,et al.  Targeting the mitotic checkpoint for cancer therapy with NMS-P715, an inhibitor of MPS1 kinase. , 2010, Cancer research.

[12]  Marc Schmidt,et al.  Ablation of the spindle assembly checkpoint by a compound targeting Mps1 , 2005, EMBO reports.

[13]  Eric F. Johnson,et al.  Discovery of potent, highly selective, and orally bioavailable pyridine carboxamide c-Jun NH2-terminal kinase inhibitors. , 2006, Journal of medicinal chemistry.

[14]  D. Zaller,et al.  Structural basis for p38α MAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity , 2003, Nature Structural Biology.

[15]  E. Gabrielson,et al.  High levels of the Mps1 checkpoint protein are protective of aneuploidy in breast cancer cells , 2011, Proceedings of the National Academy of Sciences of the United States of America.

[16]  R. Medema,et al.  Mps1 Phosphorylates Borealin to Control Aurora B Activity and Chromosome Alignment , 2008, Cell.

[17]  Huai Gao,et al.  The Discovery of VX-745: A Novel and Selective p38α Kinase Inhibitor. , 2011, ACS medicinal chemistry letters.

[18]  D. Zaller,et al.  Structural basis for p38alpha MAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity. , 2003 .

[19]  Gavin Harper,et al.  Assessment of chemical coverage of kinome space and its implications for kinase drug discovery. , 2008, Journal of medicinal chemistry.

[20]  Lionel Arnaud,et al.  Human Mps1 kinase is required for the spindle assembly checkpoint but not for centrosome duplication , 2002, The EMBO journal.

[21]  R. Syed,et al.  3-amino-7-phthalazinylbenzoisoxazoles as a novel class of potent, selective, and orally available inhibitors of p38alpha mitogen-activated protein kinase. , 2008, Journal of medicinal chemistry.

[22]  Luping Liu,et al.  Design and synthesis of potent, orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase. , 2003, Bioorganic & medicinal chemistry letters.

[23]  Li Xing,et al.  Structural bioinformatics-based prediction of exceptional selectivity of p38 MAP kinase inhibitor PH-797804. , 2009, Biochemistry.

[24]  Matthew R. Lee,et al.  Discovery of pyridazinopyridinones as potent and selective p38 mitogen-activated protein kinase inhibitors. , 2010, Journal of medicinal chemistry.

[25]  Aaron Rogers,et al.  Characterization of the Cellular and Antitumor Effects of MPI-0479605, a Small-Molecule Inhibitor of the Mitotic Kinase Mps1 , 2011, Molecular Cancer Therapeutics.

[26]  M. Winey,et al.  Human Mps1 protein kinase is required for centrosome duplication and normal mitotic progression , 2003, Proceedings of the National Academy of Sciences of the United States of America.